Nu-tertiary amino-alkylene 4-or 5-nitroimidazoles and their preparation



United States Patent 3,399,193 N -TERTIARY AMINO-ALKYLENE 4- 0R S-NITRO-IMIDAZOLES AND THEIR PREPARATION Pier Nicola Giraldi and VittorioMariotti, Milan, Italy,

assignors to Carlo Erba S.p.A., Milan, Italy, a corporation of Italy NoDrawing. Filed Aug. 4, 1965, Ser. No. 477,318

7 Claims. (Cl. 260-2475) ABSTRACT OF THE DISCLOSURE Newimidazole-derivatives, and the process for making the same, aredisclosed. These derivatives are made by reacting metal salts of 4- orS-nit-ro-imidazole with phalageno-ethyl-(morpholine, pyrrolidine, ordimethyl amine). The imidazole-derivatives exhibit antitrichomonasactivity.

This patent relates to preparation of new imidazolederivatives withamine side chain, having following general formula:

-N om t j N Br where A is an either branched or not-branched aliphaticchain with 1 to 6 C atoms, R, and R are either identical to or differentfrom each other, and represent H, aliphatic chains either branched ornot, substituted or not, aryl-, alkyl-aryl radicals, and can be a partof a heterocyclic ring.

The position of the nitro-group can be in positions 4 or 5; the isomerscan be separated by means of fractionated crystallization.

These substances can be prepared for example by reaction of metal salts,preferably sodium or silver salts, of 4(5)-nitro-imidazole withsubstances having following formula:

where A, R, and R have the aforementioned meanings, in dry solvents suchas xylene, toluene, etc.

Some compounds of those thus synthesized show a considerable in vivo andin vitro activity on many protozoa, particularly marked on Trichomonasvaginalis. In addition to this, substances of this class, such as forinstance N-fi-ethyl-morpholino-MS)-nitro-imidazole show a goodsolubility in water, much higher than that owned by similar productsactive on Trichomronas vaginalis such as e.g.,N-B-oxy-ethyl-Z-methyl-S-nitro-imidazole.

This makes resorption of substances considerably easier when in vivoadministration is required, with successive quick removal avoidingharmful accumulation phenomena. Following examples illustrate but do notlimit the subject invention:

EXAMPLE 1 6 g. 4'(5)-nitro-imidazole sodium salt and 9 g. [SI-chloro-3,399,193 Patented Aug. 27, 1968 ice ethyl-morpholine are allowed toreact in 200 m1. dry toluene. The mixture is refluxed for 50 hr., thencooled and filtered from the solid residue. The solvent is evaporatedunder reduced pressure. The half-solid product thus obtained solidifiesby addition of petroleum ether and ethyl ether.

Crystallization from water results inN-fl-ethyl-rnorpholino-(5)-nitro-imidazole (M.P. 11l C.); from motherliquors N-B-ethyl-morpholino-(4)-nitro-imidazole (M.P. l04-106 C.) isobained.

EXAMPLE 2 4.2 g. 4(5)-nitro-imidazole sodium salt and 4.02 g.pchloro-ethyl-pyrrolidine are refluxed in ml. dry toluene for 24 hr.,then the solid residue is filtered, and the solvent is evaporated underreduced pressure. The so obtained oil solidifies by adding petroleumether.

Crystallization from hexane results in a mixture of N- 8 ethylpyrrolidino (5) nitro imidazole and N B- ethyl-pyrrolidino- (4-nitro-imidazole.

EXAMPLE 3 3.4 g. 4(5)-nitro-imidazole and 3.2 g.N-fi-diethylaminoethyl-chloride are refluxed for 24 hours in 120 ml. drytoluene. After filtration and evaporation of the solvent, the residueoil is dissolved in ethanol and treated with bone charcoal. The residuethus obtained solidifies by addition of hexane.

Crystallization from hexane results in a mixture of N- B diethyl aminoethyl (5) nitro imidazole andN-fi-diethyl-amino-ethyl-(4)-nitro-imidazole.

We claim:

. N-[i-diethyl-amino-ethyl-(5)-nitro-imidazole.

. N-B-diethyl-amino-ethyl-(4) -nitro-imidazole.

. N-fi-morpholino-ethyl-( 5)-nitro-imidazo1e.

. N-fl-morpholino-ethyl-(4)-nitro-imidazole.

. N-fi-pyrrolidino-ethyh 5 -nitro-imidazole.

. N- s-pyrrolidino-ethyl-(4)-nitro-imidazole.

. A process for preparing imidazole-derivatives of the formula --N o 2NJ wherein A is alkylene of 1 to 6 carbon atoms and R and R are ethyl or,when taken together, along with the N- atom, are morpholino orpyrrolidino, and the nitro group is in the 4 or 5 position, by reactingmetal salts of 4(5)- nitroimidazole, in suitable solvent,, withcompounds having the formula:

wherein A, R, and R have been previously defined and thereafterseparating the resultant nitro-isomers by tractional crystallization.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner.

JOSE TOVAR, Assistant Examiner.

